Indomethacin, because of its prostaglandin inhibition, may cause constriction of the ductus arteriosus and affect the pulmonary circulation. To study this possibility, we gave indomethacin daily by gavage to two groups of pregnant rats from the 17th day of pregnancy through delivery (group 1, 2 mg/kg/day; group 2, 4 mg/kg/day). Group 3, untreated control pregnant rats received saline. The pups were killed 30 min after birth and heart-lung preparations were perfused with glutaraldehyde. Appropriate blocks were processed for quantitative morphometry of the pulmonary arteries and arterioles. For analysis, the vessels were grouped by external diameter, i.e., less than 30, 30 to 50, and 50 to 100 micron. Groups 1 and 2 showed an increased medial smooth muscle mass in both 30 to 50 and 50 to 100-micron vessels as indicated by media thickness and medial areas (P less than 0.05). Muscularized arterioles, less than 30 micron, were present in groups 1 and 2, but not in controls. The relative mass of lung parenchymal components were determined by point counting. Indomethacin-treated animals had an increased saccular wall mass, decreased airspace mass, and a decreased capillary to saccular wall ratio (P less than 0.05). These results show that the fetal pulmonary circulation's response to indomethacin comprises the appearance of medial hypertrophy and newly muscularized arterioles. When these changes occur in lungs with immature, thick saccular walls, there is a decreased surface for oxygen exchange and an increased pulmonary vascular resistance resulting in a persistent fetal circulation.